Multiple classes of human intracellular Heme-binding proteins with pathology-associated polymorphisms of heme...

Heme (Iron II-Protoporphyrin IX) is the pigment of life in all organisms and as a prosthetic group in vital hemoproteins contributes to pleiotropic molecular activities. In blood plasma, free heme is scavenged by hemopexin, albumin and several other proteins, while its biosynthesis, intracellular content and trafficking are normally monitored, and tightly regulated by an extensive network of diverse heme-binding proteins (HeBPs). The proteomic identification of numerous human HeBPs in recent studies prompted us to review, whether any of the identified HeBPs carry heme-binding motifs (HBMs) that exhibit genetic variations associated with pathologies. We improvised on a stepwise analytical methodology to identify HeBPs carrying disease-associated genetic (Single Nucleotide Polymorphisms-SNPs) and epigenetic (Post Translational Modifications-PTMs) variation within HBMs. Using the UniProt protein database, the HeMoQuest-WESA algorithms as well as the dbSNP, ClinVar and PhosphoSitePlus databases, we identified 1250 unique intracellular HeBPs containing 265 species with pathology-associated SNPs within putative HBMs. Among those, 136 exhibit pathology-associated polymorphisms in central heme coordinating residue positions of HBMs. We have noted over 15 protein classes of HeBPs with 377 encoded heme coordinating pathology polymorphisms, that based on population minor allele frequency (MAF) ratios, include 227 rare (<1 % MAF) and 4 common (>5 % MAF) variants. Among the latter is the cochaperone BAG3 rs2234962 that introduces the C151R substitution and varies considerably among populations. In addition, 3 more common variants were identified for the HeBPs CAST (rs754615), SERPINB8 (rs3826616) and DUOX2 (rs57659670). Also, 15 variants in 10 genes, including the Tyrosine-protein kinase ABL1 rs1060499547 (Y226C), introduce substitutions of Tyrosines (Y) normally phosphorylated. As substitutions and epigenetic marks can significantly alter the interactions of heme with HBMs, we propose that such variations can be associated with clinical pathologies.